Abstract
Alternative lengthening of telomeres (ALT) is a recombination-mediated process that maintains telomeres in telomerase-negative cancer cells. In asynchronously dividing ALT-positive cell populations, a small fraction of the cells have ALT-associated promyelocytic leukemia nuclear bodies (APBs), which contain (TTAGGG)n DNA and telomere-binding proteins. We found that restoring p53 function in ALT cells caused p21 up-regulation, growth arrest/senescence, and a large increase in cells containing APBs. Knockdown of p21 significantly reduced p53-mediated induction of APBs. Moreover, we found that heterochromatin protein 1 (HP1) is present in APBs, and knockdown of HP1alpha and/or HP1gamma prevented p53-mediated APB induction, which suggests that HP1-mediated chromatin compaction is required for APB formation. Therefore, although the presence of APBs in a cell line or tumor is an excellent qualitative marker for ALT, the association of APBs with growth arrest/senescence and with "closed" telomeric chromatin, which is likely to repress recombination, suggests there is no simple correlation between ALT activity level and the number of APBs or APB-positive cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Antigens, Viral, Tumor / metabolism
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Cell Line
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Cellular Senescence / genetics
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Cellular Senescence / physiology
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Chromobox Protein Homolog 5
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Chromosomal Proteins, Non-Histone / metabolism
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Chromosomal Proteins, Non-Histone / physiology*
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Cyclin-Dependent Kinase 2 / analysis
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Cyclin-Dependent Kinase 2 / metabolism
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Cyclin-Dependent Kinase Inhibitor p21 / physiology
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Humans
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Nuclear Proteins / analysis
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Nuclear Proteins / metabolism
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RNA Interference
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Telomere / metabolism*
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Telomeric Repeat Binding Protein 1 / analysis
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Telomeric Repeat Binding Protein 2 / analysis
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Tumor Suppressor Protein p53 / metabolism
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Tumor Suppressor Protein p53 / physiology*
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Up-Regulation
Substances
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Adaptor Proteins, Signal Transducing
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Antigens, Viral, Tumor
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CBX5 protein, human
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Chromosomal Proteins, Non-Histone
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Cyclin-Dependent Kinase Inhibitor p21
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Nuclear Proteins
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PCNP protein, human
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TERF2 protein, human
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Telomeric Repeat Binding Protein 1
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Telomeric Repeat Binding Protein 2
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Tumor Suppressor Protein p53
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Chromobox Protein Homolog 5
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CDK2 protein, human
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Cyclin-Dependent Kinase 2